This application constitutes the request to transition to the ROO phase of a K99 Pathway to Indepentdence Awarid aimed at fostering and expanding ail the inter-related components of a academic career in basic and applied aspects of human aging. Dr. IVladalena Costa's long-term research goals are: (i) to understand basic mechanisms of nonlinear biologic and physiologic control in health and their degradation with aging and frailty, (ii) to develop a new class of dynamical biomarkers that quantify integrative function and give information about pathophysiology not obtainable with traditional probes, and (iii) to determine the value of this new class of dynamical biomarlcers for risk stratification and the assessment of therapeutic interventions designed to reverse or retard pathologic aging. Her work is at the interfaces of statistical physics, bioengineering, physiology, and the biology of aging. Two emerging themes of this interdisciplinary work are that healthy systems, which are marked by robustness and adaptability, exhibit the most complex multiscale dynamics, and that aging and the frailty syndrome in particular, are marked by a loss of complex multiscale variability and adaptive capacity. Dr. Costa's K99 award has allowed her to become an independent investigator working at the interface between complex systems and the biologic of aging. Her specific research aims for the ROO phase as presented in the original proposal remain unchanged. Propelled by the foundational K99 training and research work. Dr. Costa is also pursuing a number of inter-related sub-projects as part of her coherent program as a full time faculty member. The specific aims are: 1) to elucidate nonlinear mechanisms of integrative physiologic control by developing dynamical biomarkers that quantify multiscale fluctuations; 2) to test the hypothesis that the dynamical complexity of physiologic regulatory mechanisms degrades with aging in representative systems ranging from the cellular to organ, and 3) to test the hypothesis that loss of complexity in physiologic systems over time can be predictive of overall health status degradation and subsequent development of frailty.